Phenoxymethylalkyne inhibitors of lta4h for treating inflammation

ABSTRACT

A chemical genus of biphenyl heterocycle derivative inhibitors of LTA4H (leukotriene A4 hydrolase) of the formula:  
                 
 
is disclosed. In these compounds Q and Z are (CH 2 ) 1-10 ; in which one or two (CH 2 ) may optionally be replaced by —O—, —NR 1 —, —SO—, —S(O) 2 —, —C(═O)— or —C═O(NH)—; Het is a 5-7 membered non-aromatic nitrogen heterocycle; and W is acyl, hydroxyl, carboxyl, amino, carboxamido, aminoacyl, —COOalkyl, —CHO, heterocyclyl, substituted aryl, or substituted heterocyclyl, or taken together ZW can be H or —COOalkyl. The compounds are useful for the treatment and prevention and prophylaxis of inflammatory diseases and disorders.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.60/821,482 filed Aug. 4, 2006, which is hereby incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to a chemical genus of biphenylheterocycle derivative inhibitors of LTA4H (leukotriene A4 hydrolase)useful for the treatment and prevention and prophylaxis of inflammatorydiseases and disorders.

BACKGROUND OF THE INVENTION

The end products of the leukotriene pathway are potent inflammatorylipid mediators derived from arachidonic acid. They can potentiallycontribute to development of atherosclerosis and destabilization ofatherosclerotic plaques through lipid oxidation and/or proinflammatoryeffects. As described elsewhere, a gene on chromosome 13q12 has beenidentified as playing a major role in myocardial infarction (MI),[Helgadottir et al., Nature Genetics doi: 10.1038/ng 1311, 8 Feb. 2004].This gene (ALOX5AP), herein after referred to as an MI disease gene,comprises nucleic acid that encodes 5-lipoxygenase activating protein(FLAP), herein after referred to as FLAP. DNA variants in the FLAP geneincrease risk for myocardial infarction by 1.8 fold and for stroke by1.7 fold. The leukotriene pathway, through FLAP, leads to the productionof leukotriene B4 by the enzyme leukotriene A4 hydrolase (LTA4H).Leukotriene B4 is one of the most potent chemokine mediators of arterialinflammation. Particular DNA variants in the gene encoding LTA4H alsoelevate risk for MI and stroke, as described elsewhere [Hakonarsson etal., J. Am. Med. Assoc. 293, 2245-2256 (2005)]. Individuals with a priorhistory of MI produce more leukotriene B4 when their isolatedneutrophils are stimulated with ionomycin. Increased LTB4 production isparticularly marked in male patients with a prior history of MI whocarry risk variants in the FLAP gene [Helgadottir et al.]. The treatment(prophylactic and/or therapeutic) of certain diseases and conditions(e.g., MI, acute coronary syndrome (ACS), stroke, atherosclerosis)associated with FLAP or with LTA4H can be accomplished by inhibitingLTA4H. Inhibiting LTA4H is advantageous for methods of treatment for MIor susceptibility to MI; for ACS (e.g., unstable angina,non-ST-elevation myocardial infarction (NSTEMI) or ST-elevationmyocardial infarction (STEMI)); for decreasing risk of a second MI; forstroke (including transient ischemic attack) or susceptibility tostroke; for atherosclerosis, such as for patients requiring treatment(e.g., angioplasty, stents, coronary artery bypass graft) to restoreblood flow in coronary arteries, such as patients requiring treatmentfor peripheral vascular disease including peripheral occlusive arterialdisease, critical limb ischemia (e.g., gangrene, ulceration), andintermittent claudication to restore blood flow in the lower limbs; foratherosclerotic reno-vascular disease; for abdominal aortic aneurysm;and/or for decreasing leukotriene synthesis (e.g., for treatment of MI).

US Patent Application Publication No. 20050043378 and 20050043379,relate to benzooxazol-2-yl, benzothiazol-2-yl and 1H-benzoimidazol-2-ylcompounds and derivatives thereof useful as leukotriene A4 hydrolase(LTA4H) inhibitors in treating inflammation and disorders associatedwith inflammation. These disclosures are incorporated herein byreference as they relate to utility.

SUMMARY OF THE INVENTION

The present invention relates to compounds exhibiting LTA4H enzymeinhibition, having general formula:

whereinR¹ is selected from the group consisting of H, alkyl, aryl, heteroaryl,aryl substituted with from one to three substituents independentlyselected from the group consisting of halogen, loweralkyl, loweracyl,loweralkoxy, fluoroloweralkyl, fluoroloweralkoxy, hydroxyloweralkyl,formyl, cyano, benzyl, benzyloxy, phenyl, heteroaryl, heterocyclylalkyland nitro; and heteroaryl substituted with from one to threesubstituents independently selected from the group consisting ofhalogen, loweralkyl, loweracyl, loweralkoxy, fluoroloweralkyl,fluoroloweralkoxy, formyl, cyano, phenyl, heteroaryl, heterocyclylalkyland nitro;Q is (CH₂)₁₋₈; in which one or two (CH₂) may optionally be replaced by—O—, —NR¹—, —SO—, —S(O)₂—, —C(═O)— or —C═O(NH)—, provided that said —O—,—NR¹—, —SO—, —S(O)₂—, —C(═O)— or —C═O(NH)— are separated by at least one—(CH₂)—; and when Het is a nitrogen-attached heterocycle, Q mayadditionally be a direct bond;Het is a 5-7 membered non-aromatic nitrogen heterocycle;Z is (CH₂)₁₋₁₀; in which one or two (CH₂) may optionally be replaced by—O—, —NR¹—, —SO—, —S(O)₂—, —C(═O)— or —C═O(NH)—, provided that said —O—,—NR¹—, —SO—, —S(O)₂—, —C(═O)— or —C═O(NH)— are not at the point ofattachment to nitrogen and are separated by at least one —(CH₂)—;W is selected from acyl, hydroxyl, carboxyl, amino, carboxamido,aminoacyl, —COOalkyl, —CHO, sulfonamide, —C(O)fluoroalkyl,—C(O)CH₂C(O)Oalkyl, —C(O)CH₂C(O)Ofluoroalkyl, —SH, —C(O)NH(OH),—C(O)N(OH)R⁴, —N(OH)C(O)OH, —N(OH)C(O)R⁴, heterocyclyl, substitutedaryl, and substituted heterocyclyl, or taken together ZW are H or—COOalkyl; andR⁴ is selected from the group consisting of H and lower alkyl.

In a second aspect the invention relates to pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of at least one of the compounds as described herein.

In a third aspect, the invention relates to methods for the treatmentand prevention or prophylaxis of a disease, condition or disorderassociated with leukotriene A4 hydrolase. The methods compriseadministering to a mammal a therapeutically effective amount of acompound described above. The disease or condition may be related toallergic, acute or chronic inflammation. The disease may be for examplecontact and atopic dermatitis, arthritis, allergic rhinitis, asthma oran autoimmune diseases such as Crohn's disease, psoriasis, ulcerativecolitis, inflammatory bowel disease, multiple sclerosis, ankylosingspondylitis, and the like. Similarly, the compounds defined above can beused in preventing recurring inflammatory attacks. The compounds arealso useful for treating and preventing atherosclerosis, thrombosis,stroke, acute coronary syndrome, stable angina, peripheral vasculardisease, critical leg ischemia, intermittent claudication, abdominalaortic aneurysm and myocardial infarction.

DETAILED DESCRIPTION OF THE INVENTION

Throughout this specification the substituents are defined whenintroduced and retain their definitions.

In one aspect the invention relates to heterocycle derivatives useful asLTA4H enzyme inhibitors, having the general formula:

In some embodiments the compounds have the formula

wherein n is 1-4 and Het is chosen from pyrrolidine, piperidine andpiperazine.

In other embodiments, Q is a direct bond and Het is a piperazine. Thesecompounds have the formula

In many embodiments Z is (CH₂)₁₋₅ and W is COOH. In many otherembodiments, R¹ is H, methyl, phenyl or substituted phenyl.

In another aspect the present invention provides pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one compound as describedabove.

Methods of the invention parallel the compositions and formulations. Themethods comprise administering to a patient in need of treatment atherapeutically effective amount of a compound according to theinvention.

The present invention provides a method for inhibiting leukotriene A4hydrolase comprising contacting the LTA4H enzyme with a therapeuticallyeffective amount of a compound according to the general formula.

Furthermore, the present invention provides a method for treating adisorder associated with leukotriene A4 hydrolase comprisingadministering to a mammal a therapeutically effective amount of acompound or a salt, hydrate or ester thereof according to the generalformula given above. It may be found upon examination that additionalspecies and genera not presently excluded are not patentable to theinventors in this application. In either case, the exclusion of speciesand genera in applicants' claims are to be considered artifacts ofpatent prosecution and not reflective of the inventors' concept ordescription of their invention. The invention, in a composition aspect,is all compounds of the general formula above, except those that are inthe public's possession. The invention, in a method aspect, is a methodemploying compounds of the general formula above, except those methodsthat are in the public's possession.

In some embodiments the disorder is associated with inflammation. Insome embodiments the disorder is selected from allergic inflammation,acute inflammation and chronic inflammation.

Compounds of the genus represented by the general formula above areinhibitors of LTA₄H enzyme. As such they have utility in treating andpreventing inflammatory diseases and disorders, as described above,particularly for such conditions as asthma, chronic obstructed pulmonarydisease (COPD), atherosclerosis, rheumatoid arthritis, multiplesclerosis, inflammatory bowel diseases (IBD)—including Crohn's diseaseand ulcerative colitis—or psoriasis, which are each characterized byexcessive or prolonged inflammation at some stage of the disease.

Recent research indicates that the compounds are also useful fortreating and preventing atherosclerosis, thrombosis, stroke, acutecoronary syndrome, stable angina, peripheral vascular disease, criticalleg ischemia, intermittent claudication, abdominal aortic aneurysm andmyocardial infarction.

The compounds may be presented as salts. The term “pharmaceuticallyacceptable salt” refers to salts whose counter ion derives frompharmaceutically acceptable non-toxic acids and bases. Suitablepharmaceutically acceptable base addition salts for the compounds of thepresent invention include, but are not limited to, metallic salts madefrom aluminum, calcium, lithium, magnesium, potassium, sodium and zincor organic salts made from lysine, N,N-dialkyl amino acid derivatives(e.g. N,N-dimethylglycine, piperidine-1-acetic acid andmorpholine-4-acetic acid), N,N′-dibenzylethylenediamine, chloroprocaine,choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine)and procaine. When the compounds contain a basic residue, suitablepharmaceutically acceptable base addition salts for the compounds of thepresent invention include inorganic acids and organic acids. Examplesinclude acetate, benzenesulfonate (besylate), benzoate, bicarbonate,bisulfate, carbonate, camphorsulfonate, citrate, ethanesulfonate,fumarate, gluconate, glutamate, bromide, chloride, isethionate, lactate,maleate, malate, mandelate, methanesulfonate, mucate, nitrate, pamoate,pantothenate, phosphate, succinate, sulfate, tartrate,p-toluenesulfonate, and the like.

For convenience and clarity certain terms employed in the specification,examples and claims are described herein.

Alkyl is intended to include linear, branched, or cyclic hydrocarbonstructures and combinations thereof. Lower alkyl refers to alkyl groupsof from 1 to 6 carbon atoms. Examples of lower alkyl groups includemethyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl and the like.Preferred alkyl groups are those of C₂₀ or below. Cycloalkyl is a subsetof alkyl and includes cyclic hydrocarbon groups of from 3 to 8 carbonatoms. Examples of cycloalkyl groups include c-propyl, c-butyl,c-pentyl, norbornyl and the like.

C₁ to C₂₀ hydrocarbon includes alkyl, cycloalkyl, alkenyl, alkynyl,aryl, arylalkyl and combinations thereof. Examples include phenethyl,cyclohexylmethyl, camphoryl, adamantyl and naphthylethyl.

Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of astraight, branched, cyclic configuration and combinations thereofattached to the parent structure through oxygen. Examples includemethoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy andthe like. Lower-alkoxy refers to groups containing one to four carbons.

Alkoxyalkyl refers to ether groups of from 3 to 8 atoms of a straight,branched, cyclic configuration and combinations thereof attached to theparent structure through an alkyl. Examples include methoxymethyl,methoxyethyl, ethoxypropyl, and the like.

Alkoxyaryl refers to alkoxy substituents attached to an aryl, whereinthe aryl is attached to the parent structure. Arylalkoxy refers to arylsubstituents attached to an oxygen, wherein the oxygen is attached tothe parent structure. Substituted arylalkoxy refers to a substitutedaryl substituent attached to an oxygen, wherein the oxygen is attachedto the parent structure.

Acyl refers to groups of from 1 to 8 carbon atoms of a straight,branched, cyclic configuration, saturated, unsaturated and aromatic andcombinations thereof, attached to the parent structure through acarbonyl functionality. One or more carbons in the acyl residue may bereplaced by nitrogen, oxygen or sulfur as long as the point ofattachment to the parent remains at the carbonyl. Examples includeacetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl,benzyloxycarbonyl and the like. Lower-acyl refers to groups containingone to four carbons.

Aryl and heteroaryl mean a 5- or 6-membered aromatic or heteroaromaticring containing 0-3 heteroatoms selected from O, N, or S; a bicyclic 9-or 10-membered aromatic or heteroaromatic ring system containing 0-3heteroatoms selected from O, N, or S; or a tricyclic 13- or 14-memberedaromatic or heteroaromatic ring system containing 0-3 heteroatomsselected from O, N, or S. The aromatic 6- to 14-membered carbocyclicrings include, e.g., benzene and naphthalene, and according to theinvention benzoxalane and residues in which one or more rings arearomatic, but not all need be. The 5- to 10-membered aromaticheterocyclic rings include, e.g., imidazole, pyridine, indole,thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline,isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.

Arylalkyl refers to a substituent in which an aryl residue is attachedto the parent structure through alkyl. Examples are benzyl, phenethyland the like. Heteroarylalkyl refers to a substituent in which aheteroaryl residue is attached to the parent structure through alkyl.Examples include, e.g., pyridinylmethyl, pyrimidinylethyl and the like.Heterocyclylalkyl refers to a substituent in which a heterocyclylresidue is attached to the parent structure through alkyl. Examplesinclude morpholinoethyl and pyrrolidinylmethyl.

Heterocycle means a cycloalkyl or aryl residue in which from one tothree carbons is replaced by a heteroatom selected from the groupconsisting of N, O and S. The nitrogen and sulfur heteroatoms mayoptionally be oxidized, and the nitrogen heteroatom may optionally bequaternized. Examples of heterocycles include pyrrolidine, pyrazole,pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline,benzofuran, benzodioxan, benzodioxole (commonly referred to asmethylenedioxyphenyl, when occurring as a substituent), tetrazole,morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene,furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran and thelike. It is to be noted that heteroaryl is a subset of heterocycle inwhich the heterocycle is aromatic. Examples of heterocyclyl residuesadditionally include piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxo-pyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidinyl,pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl,oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl,quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl,benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl,thienyl, benzothienyl, thiamorpholinyl, thiamorpholinylsulfoxide,thiamorpholinylsulfone, oxadiazolyl, triazolyl and tetrahydroquinolinyl.

An oxygen heterocycle is a heterocycle containing at least one oxygen inthe ring; it may contain additional oxygens, as well as otherheteroatoms. A sulphur heterocycle is a heterocycle containing at leastone sulphur in the ring; it may contain additional sulphurs, as well asother heteroatoms. A nitrogen heterocycle is a heterocycle containing atleast one nitrogen in the ring; it may contain additional nitrogens, aswell as other heteroatoms. Oxygen heteroaryl is a subset of oxygenheterocycle; examples include furan and oxazole. Sulphur heteroaryl is asubset of sulphur heterocycle; examples include thiophene and thiazine.Nitrogen heteroaryl is a subset of nitrogen heterocycle; examplesinclude pyrrole, pyridine and pyrazine. A saturated nitrogenousheterocycle is a subset of nitrogen heterocycle. Saturated nitrogenousheterocycle contain at least one nitrogen and may contain additionalnitrogens, as well as other heteroatoms. Examples include pyrrolidine,pyrazolidine, piperidine, morpholine, and thiomorpholine.

Substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to alkyl,aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in eachresidue are replaced with halogen, haloalkyl, hydroxy, loweralkoxy,carboxy, carboalkoxy (also referred to as alkoxycarbonyl), carboxamido(also referred to as alkylaminocarbonyl), cyano, carbonyl, nitro, amino,alkylamino, dialkylamino, mercapto, alkylthio, sulfoxide, sulfone,acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, orheteroaryloxy.

The terms “halogen” and “halo” refer to fluorine, chlorine, bromine oriodine.

The term “prodrug” refers to a compound that is made more active invivo. Activation in vivo may come about by chemical action or throughthe intermediacy of enzymes. Microflora in the GI tract may alsocontribute to activation in vivo.

It will be recognized that the compounds of this invention can exist inradiolabeled form, i.e., the compounds may contain one or more atomscontaining an atomic mass or mass number different from the atomic massor mass number usually found in nature. Radioisotopes of hydrogen,carbon, phosphorous, fluorine, and chlorine include ²H, ³H, ¹³C, ¹⁴C,¹⁵N, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds that contain thoseradioisotopes and/or other radioisotopes of other atoms are within thescope of this invention. Tritiated, i.e. ³H, and carbon-14, i.e., ¹⁴C,radioisotopes are particularly preferred for their ease in preparationand detectability. Radiolabeled compounds of formula of this inventionand prodrugs thereof can generally be prepared by methods well known tothose skilled in the art. Conveniently, such radiolabeled compounds canbe prepared by carrying out the procedures disclosed in the Examples andSchemes by substituting a readily available radiolabeled reagent for anon-radiolabeled reagent.

As used herein, and as would be understood by the person of skill in theart, the recitation of “a compound” is intended to include salts,solvates, co-crystals and inclusion complexes of that compound.

The term “solvate” refers to a compound of formula I in the solid state,wherein molecules of a suitable solvent are incorporated in the crystallattice. A suitable solvent for therapeutic administration isphysiologically tolerable at the dosage administered. Examples ofsuitable solvents for therapeutic administration are ethanol and water.When water is the solvent, the solvate is referred to as a hydrate. Ingeneral, solvates are formed by dissolving the compound in theappropriate solvent and isolating the solvate by cooling or using anantisolvent. The solvate is typically dried or azeotroped under ambientconditions. Co-crystals are combinations of two or more distinctmolecules arranged to create a unique crystal form whose physicalproperties are different from those of its pure constituents.Pharmaceutical co-crystals have recently become of considerable interestfor improving the solubility, formulation and bioavailability of suchdrugs as itraconazole [see Remenar et al. J. Am. Chem. Soc. 125,8456-8457 (2003)] and fluoxetine. Inclusion complexes are described inRemington: The Science and Practice of Pharmacy 19^(th) Ed. (1995)volume 1, page 176-177. The most commonly employed inclusion complexesare those with cyclodextrins, and all cyclodextrin complexes, naturaland synthetic, with or without added additives and polymer(s), asdescribed in U.S. Pat. Nos. 5,324,718 and 5,472,954, are specificallyencompassed within the claims. The disclosures of Remington and the '718and '954 patents are incorporated herein by reference.

[The compounds described herein may contain asymmetric centers and maythus give rise to enantiomers, diastereomers, and other stereoisomericforms. Each chiral center may be defined, in terms of absolutestereochemistry, as (R)— or (S)—. The present invention is meant toinclude all such possible isomers, as well as, their racemic andoptically pure forms. Optically active (R)— and (S)— isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. The prefix “rac” refers to a racemate. When thecompounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended that the compounds include both E and Z geometric isomers. Therepresentation of the configuration of any carbon-carbon double bondappearing herein is selected for convenience only, and unless explicitlystated, is not intended to designate a particular configuration. Thus acarbon-carbon double bond depicted arbitrarily as E may be Z E, or amixture of the two in any proportion. Likewise, all tautomeric forms arealso intended to be included.

The graphic representations of racemic, ambiscalemic and scalemic orenantiomerically pure compounds used herein are taken from Maehr J.Chem. Ed. 62, 114-120 (1985): solid and broken wedges are used to denotethe absolute configuration of a chiral element; wavy lines and singlethin lines indicate disavowal of any stereochemical implication whichthe bond it represents could generate; solid and broken bold lines aregeometric descriptors indicating the relative configuration shown butdenoting racemic character; and wedge outlines and dotted or brokenlines denote enantiomerically pure compounds of indeterminate absoluteconfiguration.

Terminology related to “protecting”, “deprotecting” and “protected”functionalities occurs throughout this application. Such terminology iswell understood by persons of skill in the art and is used in thecontext of processes that involve sequential treatment with a series ofreagents. In that context, a protecting group refers to a group, whichis used to mask a functionality during a process step in which it wouldotherwise react, but in which reaction is undesirable. The protectinggroup prevents reaction at that step, but may be subsequently removed toexpose the original functionality. The removal or “deprotection” occursafter the completion of the reaction or reactions in which thefunctionality would interfere. Thus, when a sequence of reagents isspecified, as it is in the processes of the invention, the person ofordinary skill can readily envision those groups that would be suitableas “protecting groups”. Suitable groups for that purpose are discussedin standard textbooks in the field of chemistry, such as ProtectiveGroups in Organic Synthesis by T. W. Greene [John Wiley & Sons, NewYork, 1991], which is incorporated herein by reference.

A comprehensive list of abbreviations utilized by organic chemistsappears in the first issue of each volume of the Journal of OrganicChemistry. The list, which is typically presented in a table entitled“Standard List of Abbreviations”, is incorporated herein by reference.

In general, the compounds of the present invention may be prepared bythe methods illustrated in the general reaction schemes as, for example,described below, or by modifications thereof, using readily availablestarting materials, reagents and conventional synthesis procedures.

EXAMPLES

Example 1

Step 1:

2-(4-Benzyloxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butylester

To a 15 mL of anhydrous DMF was added NaH (60% dispersion in oil, 338mg, 8.44 mmol), and the resulting reaction mixture was cooled to 0° C.p-benzyloxy phenol (1.41 g, 7.03 mmol) was added and the reactionmixture was stirred at rt for 45 min. It was then cooled to −5° C., and(R)-Boc-prolinol tosylate (2.5 g, 7.03 mmol) in anhydrous DMF (5 mL) wascooled in a separate ice-bath and added dropwise to the reactionmixture. It was then allowed to warm to rt and stirred at 92° C. for 5 hand at rt overnight. The resulting mixture was poured into 200 mLice/water and stirred for an hour. The resulting precipitate wasfiltered, washed with ether, dried over MgSO₄, concentrated,recrystallized with ether/hexane to give shiny yellow crystals (1.5 g,55%).

Step 2:

2-(4-Hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butylester

A solution of the product from step 1, in THF (1 ml), EtOH (25 ml), Pd—C(1.17 g, 10% wt) in a round bottom flask was charged with H₂-balloonafter flushing with hydrogen 3 times. The resulting solution was stirredovernight at rt. The reaction mixture was then filtered, washed with THF(30 ml), EtOH (25 ml) and dried over anhydrous MgSO₄. After removal ofthe solvent in vacuo, the product was obtained as an orange oil (1.0 g,95%).

Step 3:

2-(4-Prop-2-ynyloxy-phenoxymethyl)-pyrrolidine-1-carboxylic acidtert-butyl ester

To a solution of the product from step 2 (2.0 g, 6.82 mmol) in anhydrousDMF (50 mL) was added dry K₂CO₃ (4.6 g, 33 mmol) and allowed to stir for15 min. Propargyl bromide (1.214 g, 10.20 mmol) in anhydrous DMF (10 mL)was added and the reaction mixture stirred at 50° C. for 6 h, then at rtfor 48 h. The reaction mixture was concentrated, taken up in EtOAc,washed with water, dried over anhydrous MgSO₄ and the solvent removed invacuo. The product was purified by silica gel flash chromatography usingEtOAc/hexane to obtain the title compound (2.0 g, 88%).

Step 4:

(R)-2-(4-Prop-2-ynyloxy-phenoxymethyl)-pyrrolidine hydrochloride

To a solution of the product from step 3 (100 mg) was added 2M HCl indioxane (4 mL) and the resulting mixture was stirred for 2 h, and thesolvent was removed in vacuo. Crude material was triturated with etherto obtain the title product (70 mg, 100%); LCMS; 97%, m/z 232.1 (M+1);¹H NMR (DMSO-d₆, 400 MHz) δ 1.70 (1H, m), 1.95 (2H, m), 2.10 (2H, m),3.20 (2H, m), 3.53 (2H, m), 3.86 (1H, m), 4.07 (1H, dd, J1=8.0 Hz,J2=10.0 Hz), 4.18 (1H, dd, J1=4.0 Hz, J2=10.8 Hz), 6.94 (4H, s), 9.2(2H, br s).

General Procedures for examples 2-4;

A: PdCl₂ (0.02 equiv), aryl iodide (1.0 equiv), H₂O (0.07 equiv), andpyrrolidine (5 equiv) were added to a flask under aerobic conditions,and the resulting mixture was stirred at 50° C. for 5 min. To thissolution was added2-(4-prop-2-ynyloxy-phenoxymethyl)-pyrrolidine-1-carboxylic acidtert-butyl ester (1.2 equiv) and the reaction mixture was stirred at 50°C. for 24 h. The reaction mixture was then extracted with EtOAc and thecombined organic layer was dried over anhydrous MgSO₄. The solvent wasremoved under vacuum, and the residue was purified by flashchromatography.

B: The product from General Procedure A was dissolved in 4.0M HCl indioxane (excess) the resulting mixture stirred for 2 h at rt. Thesolvent was removed in vacuo to obtain a thick oil. The oil wastriturated with ether to obtain the product as the HCl salt.

Example 2

Step 1:

2-[4-(3-Phenyl-prop-2-ynyloxy)-phenoxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester

General procedure A was followed using the product from step 3, Example1 (165 mg, 0.498 mmol), iodobenzene (85 mg, 0.416 mmol), PdCl₂ (2.5 mg,0.014 mmol), pyrrolidine (0.2 mL, 2.37 mmol), water (0.53 mL) to givethe title compound (30 mg, 15%).

Step 2:

2-[4-(3-Phenyl-prop-2-ynyloxy)-phenoxymethyl]-pyrrolidine

General procedure B was followed using the product from step 1, Example2 (30 mg, 0.074 mmol) to give the title compound (13 mg, 51%); MS; m/z308 (M+H) 99%; ¹H NMR (DMSO, 400 MHz) δ 1.68-2.12 (4H, m), 3.19 (2H, m),4.98 (2H, s), 6.96 (2H, d, J=9.6 Hz), 7.01 (2H, d, J=5.2 Hz), 7.42 (4H,m), 6.96 (2H, d, J=9.6 Hz), 7.01 (2H, d, J=5.2 Hz), 7.42 (4H, m).

Example 3

Step 1:

2-{4-[3-(4-Hydroxymethyl-phenyl)-prop-2-ynyloxy]-phenoxymethyl}-pyrrolidine-1-carboxylicacid tert-butyl ester

General procedure A was followed using the product from step 3 Example 1(266 mg, 1.0546 mmol), p-iodobenzylalcohol (156.5 mg, 0.669 mmol), PdCl₂(2.5 mg, 0.014 mmol), pyrrolidine (0.277 mL, 3.34 mmol), water (0.844mL) to give the title compound (60 mg, 20.5%).

Step 2:

(4-{3-[4-(Pyrrolidin-2-ylmethoxy)-phenoxy]-prop-1-ynyl}-phenyl)-methanol

General procedure B was followed using the product from step 1, Example3 (100 mg, 0.21 mmol) to give the title compound (30 mg, 54%); MS m/z338 (M+H)>95%; ¹H NMR (DMSO-d₆, 400 MHz) δ 1.68-2.11 (4H, m), 3.20 (2H,m), 3.87 (1H, m), 4.20 (1H, dd, J=4.0 Hz, 10.8 Hz), 4.50 (2H, d, J=5.6Hz), 4.97 (2H, s), 5.28 (OH, t, J=5.6 Hz), 6.96 (2H, d, J=9.2 Hz), 7.01(2H, d, J=6.4 Hz), 7.32 (2H, d, J=8.8 Hz), 7.38 (2H, d, J=8.0 Hz).

Example 4

Step 1:

2-{4-[3-(4-Bromo-phenyl)-prop-2-ynyloxy]-phenoxymethyl}-pyrrolidine-1-carboxylicacid tert-butyl ester

General procedure A was followed using the product from step 3 Example 1(266 mg, 0.803 mmol), p-bromo iodobenzene (156.5 mg, 0.669 mmol), PdCl₂(2.5 mg, 0.014 mmol), pyrrolidine (0.277 mL, 3.34 mmol), water (0.844mL) to give the title compound (110 mg, 33.8%).

Step 2:

2-{4-[3-(4-Bromo-phenyl)-prop-2-ynyloxy]-phenoxymethyl}-pyrrolidinehydrochloride

General procedure B was followed using the product from step 1, Example4 (100 mg, 0.21 mmol) to give the title compound. (92 mg, 96%); MS m/z423 (M+H) 99%: ¹H NMR (DMSO, 400 MHz) δ 1.68-2.13 (4H, m), 3.20 (2H, m),3.85 (1H, m), 4.06 (1H, dd, J=4.0 Hz, 10.8 Hz), 4.20 (1H, dd, J=104 Hz,3.6 Hz), 4.97 (2H, s), 6.95 (2H, d, J=8.8 Hz), 7.01 (2H, d, J=9.2 Hz),7.37 (2H, d, J=8.4 Hz), 7.59 (2H, d, J=8.4 Hz).

Example 5

Step 1:

3-[4-(4-Hydroxy-phenyl)-piperazin-1-yl]-butyric acid methyl ester

To a mixture of 4-piperazin-1-yl-phenol (2 g, 11.2 mmol) and methyl3-bromo-butyrate (2.03 g, 11.2 mmol) in DMF (5 mL) was addedtriethylamine (4.5 mL, 11.53 mmol) dropwise and the reaction mixture wasstirred at ambient temperature overnight. The mixture was poured ontowater and extracted with ethyl acetate (50 ml×3). The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄ andevaporated under vacuum to dryness. The residue was purified by silicagel flash chromatography (1% methanol in CH₂Cl₂) to furnish the titlecompound (1.85 g, 59.3%); MS; m/z 279 (M+H).

Step 2:

3-[4-(4-Prop-2-ynyloxy-phenyl)-piperazin-1-yl]-propionic acid methylester

To a mixture of the compound from step 1 (278 mg, 1.0 mmol) and K₂CO₃(152 mg, 1.1 mmol) in DMF (5 mL) was added 3-bromopropyne (130 mg, 1.1mmol) dropwise at rt. The reaction mixture was stirred at rt overnightand then partitioned between water and ethyl acetate. The organic payerswere combined and washed with brine, dried over anhydrous Na₂SO₄ andevaporated under vacuum to give a brown oil. The crude product waspurified by silica gel flash chromatography (30% ethyl acetate inhexane) to furnish the title compound (120 mg, 38%) as a light yellowsolid; MS; m/z 317 (M+H).

Step 3:

3-[4-(4-Prop-2-ynyloxy-phenyl)-piperazin-1-yl]-propionic acid sodiumsalt

The compound from step 2 (175 mg, 0.55 mmol) was dissolved in methanol(4 mL) followed by addition of 1N NaOH aqueous solution (0.55 ml, 0.55mmol). The reaction solution was stirred at 60-70° C. for 4 h and thenevaporated under vacuum to dryness. The residue was stirred with ethylacetate (4 mL) and the solid was collected by filtration and washed withethyl acetate to give the title product as an off-white solid (75 mg,42%); MS; m/z 289 (M+H).

Example 6

Step 1:

4-But-2-ynyloxy-phenol

To a solution containing butynyl bromide (1 g, 7.5 mmol), hydroquinone(827 mg, 7.5 mmol), and K2CO3 (1.o4 g, 7.5 mmol) was refluxed for 10 h.Solvent was removed in vacuo and the crude product was dissolved inEtOAc and partitioned with water. Organic layer was separated and washedwith water and dried over anhydrous Na2SO4. The solvent was removed invacuo to obtain the crude product (0.3 g, 25%), which was used for thenext step without further purification; LCMS 99%, m/z 162.2 (M⁺).

Step 2:

1-[2-(4-But-2-ynyloxy-phenoxy)-ethyl]-piperidine

To a solution of the product from step 1 (200 mg, 1.23 mmol) in MeOH (10mL) was added piperidine ethyl chloride hydrochloride (227 mg, 1.23mmol), and K2CO3 (679 mg, 4.92 mmol), and the resulting mixture wasrefluxed for 10 h. Solvent was removed in vacuo and the crude productwas dissolved in EtOAc and partitioned with water. Organic layer wasseparated and dried over anhydroua Na2SO4. Solvent was removed in vacuoto obtain a thick oil, which was added 2M HCl in ether. Solvent wasdecanted and the solid was triturated with ether to obtain the titleproduct (100 mg, 30%); MS m/z 274.4 (M+H) 99%: ¹H NMR (DMSO-d₆, 400 MHz)δ 1.39 (1H, m), 1.67-1.82 (8H, m), 2.97 (2H, m), 3.41-3.50 (1H, m), 3.75(1H, br m), 4.31 (2H, d, J=5.2 Hz), 4.67 (2H, s).

In these reactions, it is also possible to make use of variants that arein themselves known, but are not mentioned here. The starting materialsare either commercially available, synthesized as described in theexamples or may be obtained by the methods well known to persons ofskill in the art.

LTA4H inhibitors have been shown to be effective anti-inflammatoryagents in pre-clinical studies. For example, oral administration ofLTA4H inhibitor SC57461 to rodents resulted in the inhibition ofionophore-induced LTB4 production in mouse blood ex vivo, and in ratperitoneum in vivo (Kachur et al., 2002, J. Pharm. Exp. Ther. 300(2),583-587). Furthermore, eight weeks of treatment with the same inhibitorcompound significantly improved colitis symptoms in a primate model(Penning, 2001, Curr. Pharm. Des. 7(3): 163-179). The spontaneouscolitis that develops in these animals is very similar to human IBD.Therefore persons of skill in the art accept that positive results inLTA4H models are predictive of therapeutic utility in this and otherhuman inflammatory diseases.

The inflammatory response is characterized by pain, increasedtemperature, redness, swelling, or reduced function, or by a combinationof two or more of these symptoms. The terms inflammation, inflammatorydiseases or inflammation-mediated diseases or conditions include, butare not limited to, acute inflammation, allergic inflammation, andchronic inflammation.

Autoimmune diseases are associated with chronic inflammation. There areabout 75 different autoimmune disorders known that may be classifiedinto two types, organ-specific (directed mainly at one organ) andnon-organ-specific (affecting multiple organs).

Examples of organ-specific autoimmune disorders are insulin-dependentdiabetes (Type I) which affects the pancreas, Hashimoto's thyroiditisand Graves' disease which affect the thyroid gland, pernicious anemiawhich affects the stomach, Cushing's disease and Addison's disease whichaffect the adrenal glands, chronic active hepatitis which affects theliver; polycystic ovary syndrome (PCOS), celiac disease, psoriasis,inflammatory bowel disease (IBD) and ankylosing spondylitis.

Examples of non-organ-specific autoimmune disorders are rheumatoidarthritis, multiple sclerosis, systemic lupus and myasthenia gravis.

Furthermore, the compounds, compositions and methods of the presentinvention are useful in treating cancer. Leukotriene synthesis has beenshown to be associated with different types of cancer includingesophageal cancer, brain cancer, pancreatic cancer, and colon cancer.

The terms “methods of treating or preventing” mean amelioration,prevention or relief from the symptoms and/or effects associated withlipid disorders. The term “preventing” as used herein refers toadministering a medicament beforehand to forestall or obtund an acuteepisode. The person of ordinary skill in the medical art (to which thepresent method claims are directed) recognizes that the term “prevent”is not an absolute term. In the medical art it is understood to refer tothe prophylactic administration of a drug to substantially diminish thelikelihood or seriousness of a condition, and this is the sense intendedin applicants' claims. As used herein, reference to “treatment” of apatient is intended to include prophylaxis. Throughout this application,various references are referred to. The disclosures of thesepublications in their entireties are hereby incorporated by reference asif written herein.

The term “mammal” is used in its dictionary sense. Humans are includedin the group of mammals, and humans would be the preferred subjects ofthe methods of.

While it may be possible for the compounds of the formula above to beadministered as the raw chemical, it is preferable to present them as apharmaceutical composition. According to a further aspect, the presentinvention provides a pharmaceutical composition comprising a compound offormula shown above, or a pharmaceutically acceptable salt or solvatethereof, together with one or more pharmaceutically carriers thereof andoptionally one or more other therapeutic ingredients. The carrier(s)must be “acceptable” in the sense of being compatible with the otheringredients of the formulation and not deleterious to the recipientthereof.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous andintraarticular), rectal and topical (including dermal, buccal,sublingual and intraocular) administration. The most suitable route maydepend upon the condition and disorder of the recipient. Theformulations may conveniently be presented in unit dosage form and maybe prepared by any of the methods well known in the art of pharmacy. Allmethods include the step of bringing into association a compound of theformula above or a pharmaceutically acceptable salt or solvate thereof(“active ingredient”) with the carrier, which constitutes one or moreaccessory ingredients. In general, the formulations are prepared byuniformly and intimately bringing into association the active ingredientwith liquid carriers or finely divided solid carriers or both and then,if necessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder (including micronized and nanoparticulate powders) or granules;as a solution or a suspension in an aqueous liquid or a non-aqueousliquid; or as an oil-in-water liquid emulsion or a water-in-oil liquidemulsion. The active ingredient may also be presented as a bolus,electuary or paste.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active ordispersing agent. Molded tablets may be made by molding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide sustained, delayed or controlled releaseof the active ingredient therein.

The pharmaceutical compositions may include a “pharmaceuticallyacceptable inert carrier”, and this expression is intended to includeone or more inert excipients, which include starches, polyols,granulating agents, microcrystalline cellulose, diluents, lubricants,binders, disintegrating agents, and the like. If desired, tablet dosagesof the disclosed compositions may be coated by standard aqueous ornonaqueous techniques, “Pharmaceutically acceptable carrier” alsoencompasses controlled release means.

Compositions of the present invention may also optionally include othertherapeutic ingredients, anti-caking agents, preservatives, sweeteningagents, colorants, flavors, desiccants, plasticizers, dyes, and thelike. Any such optional ingredient must, of course, be compatible withthe compound of the invention to insure the stability of theformulation. The dose range for adult humans is generally from 0.1 μg to10 g/day orally. Tablets or other forms of presentation provided indiscrete units may conveniently contain an amount of compound of theinvention which is effective at such dosage or as a multiple of thesame, for instance, units containing 0.1 mg to 500 mg, usually around 5mg to 200 mg. The precise amount of compound administered to a patientwill be the responsibility of the attendant physician. However, the doseemployed will depend on a number of factors, including the age and sexof the patient, the precise disorder being treated, and its severity.The frequency of administration will depend on the pharmacodynamics ofthe individual compound and the formulation of the dosage form, whichmay be optimized by methods well known in the art (e.g. controlled orextended release tablets, enteric coating etc.).

Combination therapy can be achieved by administering two or more agents,each of which is formulated and administered separately, or byadministering two or more agents in a single formulation. Othercombinations are also encompassed by combination therapy. For example,two agents can be formulated together and administered in conjunctionwith a separate formulation containing a third agent. While the two ormore agents in the combination therapy can be administeredsimultaneously, they need not be. For example, administration of a firstagent (or combination of agents) can precede administration of a secondagent (or combination of agents) by minutes, hours, days, or weeks.Thus, the two or more agents can be administered within minutes of eachother or within any number of hours of each other or within any numberor days or weeks of each other. In some cases even longer intervals arepossible.

While in many cases it is desirable that the two or more agents used ina combination therapy be present in within the patient's body at thesame time, this need not be so. Combination therapy can also include twoor more administrations of one or more of the agents used in thecombination. For example, if agent X and agent Y are used in acombination, one could administer them sequentially in any combinationone or more times, e.g., in the order X-Y-X, X-X-Y, Y-X-Y, Y-Y-X,X-X-Y-Y, etc.

As LTA4H inhibitors, the compounds of formula above have utility intreating and preventing inter alia inflammation. The compounds andcompositions can be used advantageously in combination with other agentsuseful in treating and preventing inflammatory conditions and fortreating and preventing atherosclerosis, thrombosis, stroke, acutecoronary syndrome, stable angina, peripheral vascular disease, criticalleg ischemia, intermittent claudication, abdominal aortic aneurysm andmyocardial infarction.

Assays to Determine Potency of LTA₄ Hydrolase Inhibitors

(1) In vitro assay testing inhibitory activity against purifiedrecombinant human LTA₄ hydroase:

A human LTA₄ hydrolase full-length cDNA clone (NM_(—)000895) waspurchased from OriGene Technologies (Rockville, Md.). The gene wasamplified by polymerase chain reaction and transferred via pDONR201 intothe bacterial expression vector pDEST17 by recombination (both plasmidsfrom Invitrogen, Carlsbad, Calif.). The resulting construct wastransformed into Escherichia coli BL21-AI (Invitrogen), and expressionwas induced by chemical induction with arabinose. The recombinant enzymewas purified by chromatography on a FPLC system (Amersham Biosciences,Uppsala, Sweden) using immobilized metal affinity chromatography (Ni-NTASuperflow, Qiagen, Hilden, Germany) and anion exchange chromatography(MonoQ HR 10/10, Amersham Biosciences).

The compounds of the invention were incubated in a series of dilutionswith 200 nM of recombinant enzyme in assay buffer (100 mM Tris-HCl, 100mM NaCl, 5 mg/ml fatty-acid free BSA, 10% DMSO, pH 8.0) for 10 min atroom temperature to allow binding between LTA₄ hydrolase and theinhibitors. LTA₄ was prepared by alkaline hydrolysis of LTA₄ methylester (Biomol, Plymouth Meeting, Pa., or Cayman Chemicals, Ann Arbor,Mich.). A solution of 10 μg of the ester was dried under a nitrogenstream and redissolved in 60 μl of a solution of 80% aceton and 20% 0.25M NaOH. After incubation for 40 min at room temperature the resultingapproximately 500 μM tock of LTA₄ was kept at −80° C. for no more than afew days prior to use.

Immediately before the assay, LTA₄ was diluted to a concentration of 10μM in assay buffer (without DMSO) and added to the reaction mixture to afinal concentration of 2 μM to initiate the enzyme reaction. Afterincubation for 120 sec at room temperature, the reaction was stopped byadding 2 volumes of chilled quenching buffer, containing acetonitrilwith 1% acetic acid and 225 nM LTB₄-d₄ (Biomol). The samples were thenkept at 4° C. over night to complete protein precipitation andcentrifuged for 15 min at 1800 g. LTB₄ formed was measured by LC-MS/MSusing LTB₄-d₄ as an internal standard and an external LTB₄ standard(Biomol) as reference. Briefly, the analyte was separated from LTB₄isomers formed by spontaneous hydrolysis of LTA₄ using isocratic elution(modified protocol from Mueller et al. (1996), J. Biol. Chem. 271,24345-24348) on a HPLC system (Waters, Milford, Mass.) and analyzed on atandem quadrupole mass spectrometer (Waters). MRM transitions followedon 2 channels were 335.2>195.3 (LTB₄) and 339.2>197.3 (LTB₄-d₄). Basedon the amounts of LTB₄ found at each inhibitor concentration, adose-response curve was fitted to the data and an IC₅₀ value wascalculated. structure example IC50 (uM)

1 B

2 A

3 A

4 B

5 B

6 BA = <5 uM,B = 5-20 uM,C = 20-30 uM

1. A compound of the formula:

wherein R¹ is selected from the group consisting of H, alkyl, aryl,heteroaryl, aryl substituted with from one to three substituentsindependently selected from the group consisting of halogen, loweralkyl,loweracyl, loweralkoxy, fluoroloweralkyl, fluoroloweralkoxy,hydroxyloweralkyl, formyl, cyano, benzyl, benzyloxy, phenyl, heteroaryl,heterocyclylalkyl and nitro; and heteroaryl substituted with from one tothree substituents independently selected from the group consisting ofhalogen, loweralkyl, loweracyl, loweralkoxy, fluoroloweralkyl,fluoroloweralkoxy, formyl, cyano, phenyl, heteroaryl, heterocyclylalkyland nitro; Q is (CH₂)₁₋₈; in which one or two (CH₂) may optionally bereplaced by —O—, —NR¹—, —SO—, —S(O)₂—, —C(═O)— or —C═O(NH)—, providedthat said —O—, —NR¹—, —SO—, —S(O)₂—, —C(═O)— or —C═O(NH)— are separatedby at least one —(CH₂)—; and when Het is a nitrogen-attachedheterocycle, Q may additionally be a direct bond; Het is a 5-7 memberednon-aromatic nitrogen heterocycle; Z is (CH₂)₁₋₁₀; in which one or two(CH₂) may optionally be replaced by —O—, —NR¹—, —SO—, —S(O)₂—, —C(═O)—or —C═O(NH)—, provided that said —O—, —NR¹—, —SO—, —S(O)₂—, —C(═O)— or—C═O(NH)— are not at the point of attachment to nitrogen and areseparated by at least one —(CH₂)—; W is selected from acyl, hydroxyl,carboxyl, amino, carboxamido, aminoacyl, —COOalkyl, —CHO, sulfonamide,—C(O)fluoroalkyl, —C(O)CH₂C(O)Oalkyl, —C(O)CH₂C(O)Ofluoroalkyl, —SH,—C(O)NH(OH), —C(O)N(OH)R⁴, —N(OH)C(O)OH, —N(OH)C(O)R⁴, heterocyclyl,substituted aryl, and substituted heterocyclyl, or taken together ZW areH or —COOalkyl; and R⁴ is selected from the group consisting of H andlower alkyl.
 2. A compound according to claim 1 of formula

wherein n is 1-4 and Het is chosen from pyrrolidine, piperidine andpiperazine.
 3. A compound according to claim 2 wherein ZW is H,—COOalkyl or Z is (CH₂)₁₋₅ and W is COOH.
 4. A compound according toclaim 3 wherein R¹ is chosen from H, methyl, phenyl and substitutedphenyl.
 5. A compound according to claim 1, wherein Q is a direct bond,of formula


6. A compound according to claim 5 wherein Z is (CH₂)₁₋₅ and W is COOH.7. A compound according to claim 6 wherein R¹ is chosen from H, methyl,phenyl and substituted phenyl.
 8. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of at least one compound according to claim
 1. 9. Amethod for inhibiting leukotriene A4 hydrolase comprising contacting theLTA4H enzyme with a therapeutically effective amount of a compoundaccording to claim
 1. 10. A method for treating a disorder associatedwith leukotriene A4 hydrolase comprising administering to a mammal atherapeutically effective amount of a compound or a salt, hydrate orester thereof according to claim
 1. 11. A method according to claim 10wherein said disorder is associated with inflammation.
 12. A methodaccording to claim 11 wherein said disorder is selected from allergicinflammation, acute inflammation and chronic inflammation.
 13. A methodaccording to claim 10 wherein said disorder is chosen from asthma,chronic obstructive pulmonary disease (COPD), rheumatoid arthritis,multiple sclerosis, inflammatory bowel diseases (IBD) and psoriasis. 14.A method according to claim 10 wherein said disorder is chosen fromatherosclerosis, thrombosis, stroke, acute coronary syndrome, stableangina, peripheral vascular disease, critical leg ischemia, intermittentclaudication, abdominal aortic aneurysm and myocardial infarction.